The long term goals of this program are to elucidate the mechanisms of control of the biosynthesis of thyrotropin- releasing hormone (TRH) in a population of neurons in the hypothalamic paraventricular nucleus (PVN) that comprise a critical component of the hypothalamic-pituitary-thyroid (HPT) axis and determine how these neurons alter their response to feedback signals by thyroid hormone during adaptive and pathological conditions that comprise the nonthyroidal illness syndrome observed in man, including fasting and infection. The importance of neuropeptide Y (NPY), agouti-related protein (AGRP), GABA, alpha-MSH and CART in mediating the regulatory role of leptin to reset the HPT axis to feedback signals by circulating thyroid hormone, will be studied. Synthetic peptides, agonists and/or antagonists will be infused individually or in combination into the cerebrospinal fluid of rats or in transgenic mice with targeted deletion of melanocortin receptors 3,4, or both 3 and 4, to determine whether the effect of fasting on the HPT axis can be replicated in fed animals or prevented in fasting animals, and/or to identify the specific receptors involved. The importance of the hypothalamic dorsomedial nucleus (DMN) as a relay nucleus to TRH neurons in the PVN via a multisynaptic pathway that involves leptin- responsive neurons in the arcuate nucleus will also be explored. The chemical mediators of DMN projections to TRH neurons in the PVN will be identified; the leptin-regulated, arcuate-DMN-PVN multisynaptic pathway to TRH neurons defined; and the role of the DMN to modulate the set point for TRH gene expression in the PVN by fasting and leptin administration determined, the latter by unilateral ablation of the DMN or microinjections of alpha-MSH into the DMN and PVN. Similarly, the importance of the brainstem nucleus tractus soitarius (NTS) in leptin-mediated regulation of the HPT axis will be studied in animals with surgical disconnection the NTS from the PVN, and by determining whether glucagon-like peptide-1 (GLP-1) alters TRH gene expression. Finally, the mechanism for suppression of the HPT axis during infection will be elucidated using endotoxin (bacterial lipopolysaccharide or LPS) to replicate the inflammatory cascade caused by infection. Direct or indirect inhibitory effects on hypophysiotropic TRH neurons will be studied by determining whether cytokine-inducible inhibitors of signaling (SOCS-1 and SOCS-3) are increased in TRH neurons in the PVN following LPS administration mediated by the negative regulator of gene transcription, STAT3beta, and/or through effects on the melanocortin signaling system, NPY, GABA, CRH and/or prostaglandins in the PVN or other loci in the brain, mediated by the cAMP-responsive modifier CREM/ICER.